Page 816 - Hematology_ Basic Principles and Practice ( PDFDrive )

702 Part VI Non-Malignant Leukocytes

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chemotactic assay systems faithfully reflect prevailing in vivo condi- Newburger, and Borregaard ). The patient’s neutrophils could not be
tions is not known. Our understanding of chemotactic disorders has made to adhere to plastic surfaces or to respond to serum-opsonized
been hampered by the limitations of these assays, just as the elucida- particles in terms of ingestion and respiratory burst activity.
tion of respiratory burst defects was obscured when the major avail- The molecular basis of LAD I is now known to result from
able assay was in vitro bacterial killing. In this section, the most mutations in the gene for the common CD18 β2 subunit for these
important and best characterized of the chemotactic disorders, LAD, three leukocyte glycoproteins, now termed β2 integrins, that belong
is discussed in detail. A brief discussion of several other clinically to the integrin superfamily of adhesion molecules. Integrins are
significant chemotactic disorders is also provided. noncovalently linked heterodimeric glycoproteins consisting of an α
and a β subunit. Within each of the eight known integrin subfamilies
the β subunit is identical (and defines the subfamily), but the α
Leukocyte Adhesion Deficiency Type I subunit varies and confers the functional specificity on the integrin.
The molecular defect in LAD involves all members of the β2 integrin
LAD type I (LAD I) is a rare AR disorder of leukocyte adhesion, subfamily: αL β 2 (CD11a/CD18), αm β 2 (CD11b/CD18), and
chemotaxis, and ingestion of C3bi-opsonized microbes as a result of αx β 2 (CD11c/CD18). CD11a/CD18 is often referred to as LFA-1
decreased or absent expression of the leukocyte β 2 integrins (Table while CD11b/CD18 is also called Mac-1, Mo1, or CR3. LAD I
50.7). 18,19 The hallmark of LAD I is the occurrence of repeated, often patients have an absent, diminished, or structurally abnormal β 2
severe bacterial and fungal infections without the accumulation of subunit (CD18; see later), and as a result, the three types of α chains
pus despite persistent granulocytosis (see Table 50.7). The molecular in the β 2 integrin subfamily cannot assemble into normal α–β
basis for LAD was first suggested by Crowley and colleagues, who heterodimers. Thus, all three β 2 integrins are moderately to severely
found that neutrophils from a patient with this clinical syndrome deficient on all leukocytes in LAD.
lacked a high-molecular-weight membrane glycoprotein (see Dinauer, The β2 integrins serve as receptors for the opsonic complement
fragment C3bi, the intercellular adhesion molecules 1 and 2 (ICAM-1
and ICAM-2) that are expressed on endothelial cells and leukocytes,
TABLE Summary of Leukocyte Adhesion Deficiency Type 1 and fibrinogen. The diminished or absent expression of β2 integrins
50.7 in LAD I leukocytes results in the failure of phagocytes to emigrate
from the bloodstream to sites of infection. The early interactions with
Incidence More than 60 patients described in literature the endothelium, termed rolling, are normal in LAD I because these
Inheritance AR are mediated by a different family of adhesion molecules known as
selectins. However, β2 integrins are responsible for the subsequent
Molecular defect An absent, diminished, or structurally tight binding of neutrophils and monocytes to ICAMs on cytokine-
abnormal β subunit (CD18) caused by one activated endothelium, and this step is therefore severely defective in
of several types of mutations in the β LAD I. Transendothelial migration is also impaired. A second major
gene; in the absence of a normal β functional defect in LAD is the failure of phagocytes to bind C3bi-
subunit, the three types of α chains in the opsonized microbes. Because CD11b/CD18 is the predominant
β 2 integrin subfamily (CD11a, b, c) cannot phagocyte receptor for this complement fragment, C3bi-mediated
assemble into normal α–β heterodimers
ingestion, degranulation, and respiratory burst activity are severely
Pathogenesis All three β 2 integrins (CD11a/CD18, CD11b/ affected in LAD. Finally, β2 integrin-dependent signals play a key
CD18, and CD11c/CD18) are deficient on role in activating neutrophils for enhanced migration, phagocytosis
all leukocytes, causing multiple of antibody-opsonized microbes, and degranulation.
abnormalities in cell function: adherence; Despite in vitro defects in lymphocyte responses dependent on
chemotaxis; and C3bi-mediated ingestion, LFA-1 (CD11a/CD18), patients with LAD I rarely have clinical
degranulation, and respiratory burst manifestations related to impaired lymphocyte function. It is believed
Clinical manifestation Persistent granulocytosis (neutrophil count: that the role CD11a/CD18 plays in lymphoid cell function can be
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12,000–100,000/mm ) compensated by other adhesion proteins (CD2, CD4, CD8, and so
Severe or moderate phenotypes depending on on).
severity of deficiency
Recurrent pyogenic infections with absent Molecular Genetics of Leukocyte Adhesion
neutrophil infiltration
Delayed umbilical cord separation Deficiency Type I
Severe gingivitis or periodontitis
The fact that LAD I involves a deficiency of all leukocyte β2 integrins
Laboratory evaluation Flow cytometric measurement of surface focused attention on the common β2 chain (CD18), and mutations
CD11b in stimulated neutrophils with in the corresponding gene, ITGB2, have been identified in all LAD
monoclonal anti-CD11b 18,19
I patients who have been analyzed at the molecular level to date.
Differential diagnosis CGD Although expression of the leukocyte integrin α subunits is normal
May be associated with severe neutrophil in LAD I, these are not transported to the cell surface because the
actin dysfunction β2 chain is absent or contains mutations that disrupt its structure or
Therapy Hematopoietic stem cell transplant in its interaction with the α subunit. Mutations in the α subunits have
clinically severe patients (CD11b <0.3% not been found thus far in patients with LAD I. The CD18 glyco-
of normal) protein has a large extracellular domain at the N terminus, a single
Aggressive use of parenteral antibiotics transmembrane domain, and a 46-residue cytoplasmic tail. As with
Possible benefit of prophylactic TMP-SMX X-linked CGD, CD18 mutations in LAD I are heterogeneous in
Prognosis Severe: high incidence of death before 2 nature and family specific, and can lead to either undetectable or low
years of age unless transplantation is (9–20% of normal) levels of α–β dimer expression that correlates
performed with the clinical severity of the disease. More than 50 different
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Moderate: can survive into 20s and 30s but mutations have now been characterized in more than 100 families.
with recurrent infections These include missense mutations, mRNA splicing defects, small
deletions, and a premature termination signal. Many patients are
AR, Autosomal recessive; CGD, chronic granulomatous disease; TMP-SMX, compound heterozygotes and have two different mutant alleles for
trimethoprim–sulfamethoxazole.
CD18. About half of patients with LAD I in whom the genetic defect